Trial Information

The AKT/mTOR pathway is a relevant target in NSCLC based on preclinical data showing aberrant pathway activation in human NSCLC tumors. Everolimus as a single agent has produced some responses as well as prolonged stable disease in both chemonaive and pre-treated NSCLC (Gridelli et al, 2008). There is interest in augmenting tumor responses to chemotherapy by the addition of mTOR inhibition. Additionally, preclinically, everolimus has shown antiangiogenic activity that appears to have different targets than direct VEGF inhibiting strategies and therefore may augment the activity of targeted VEGF inhibitors (Lane et al, 2009). Therefore, we propose to study in a Phase 1 dose escalation design the addition of everolimus in escalating doses in combination with Pem/Carbo/Bev in non-squamous histology NSCLC.

Patients will be entered onto dosing cohorts of 3 patients according to the following dose escalation scheme. The first cohort will begin at dose level 1. At least three patients on each dose level must have completed cycle one before the study leadership (principal investigators, study statisticians) will allow patients to be enrolled onto the successive dose level.

Dose Level (K): 1, 2, 3

Pemetrexed (mg/m²): 500, 500, 500

Carboplatin (AUC): 5, 6, 6

Bevacizumab (mg/kg): 15, 15, 15

Everolimus (mg/day): 2.5, 2.5, 5.0

Dose-limiting toxicities (DLTs) will be defined according to the National Cancer Institute's CTCAE v.4.0 toxicity scale (see Section 3.3 below). The traditional "3+3" dosing scheme will be used for dose escalation.

When the potential MTD has been identified, it will be expanded to a total of 12 patients.

1.

Inclusion Criteria:

4. At least one measurable site of disease according to RECIST criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.

8. Adequate hepatic, renal, and chemistry function as evidenced by the following laboratory parameters collected ≤ 14 days prior to enrollment:

- serum bilirubin ≤1.5 IULN,

- AST (SGOT) or ALT (SGPT) ≤ 2.5 IULN, and

- Calculated or measured creatinine clearance ≥ 50 ml/min

9. INR ≤ 1.5 within 14 days prior to enrollment. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight heparin for >2 weeks at time of study entry). aPTT no greater than IULN

12. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed.

13. No prior treatment with everolimus. Prior treatment with pemetrexed or carboplatin is allowed, provided no disease progression with prior exposure to drugs. Prior treatment with bevacizumab allowed.

2. Exclusion Criteria:

1. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol

2. Clinically significant cardiac event such as Myocardial infarction; New York Heart Association (NYHA) classification of heart disease ≥ 2 within 3 months before study enrollment; or presence of cardiac disease that in the opinion of the Investigator increase the risk of ventricular arrhythmia.

9. Bleeding diathesis or significant coagulopathy (assuming not on anti-coagulation); patients with a history of DVT and/pr pulmonary embolism are excluded

10. Serious non-healing wound, ulcer, or bone fracture

11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment, or anticipation of need for major surgical procedure during the course of the study. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1.

12. Untreated brain metastases (treated brain metastases allowed if stable clinically and radiographically by post-treatment MRI or CT brain at least 14 days after completion of radiotherapy). Resolution of radiation-related toxicity to ≤ gr 1, and not requiring glucocorticoids for symptom management

13. Radiotherapy to systemic disease less than 28 days prior to registration. Side effects due to radiotherapy must have resolved to ≤ gr 1

14. Gross hemoptysis of ≥ 5 ml within 3 months prior to enrollment

15. ≥ Grade 2 proteinuria

16. Significant hyperlipidemia

17. Previous or current malignancies of other histologies within the last 3 years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin

18. Prior treatment with any investigational drug within the preceding 4 weeks prior to enrollment

- Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.

24. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus.

25. Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)

26. Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients aa. History of noncompliance to medical regimens ab. Patients unwilling to or unable to comply with the protocol

Type of Study:

Study Design:

Outcome Measure:

Maximum Tolerated Dose (MTD) and Recommended Phase Two Dose (RPTD) of the combination of everolimus with pemetrexed, carboplatin, and bevacizumab in patients with Stage IV non-squamous NSCLC.

Outcome Description:

Measured by adverse event profile at the end of Cycle 1. MTD is the highest dose level where less than one third of 12 evaluable patients experience a dose limiting toxicity as defined by the protocol.

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